Abstract
BackgroundWhile the immune pathogenesis caused by hepatitis B virus (HBV) infection has been studied extensively, little is known about direct pathogenic effects of HBV surface proteins. Here, we have investigated pathological cellular effects of HBV surface protein expression in the liver of transgenic mice with different genetic background.MethodsThe impact of HBV surface protein expression on the liver was studied in two mouse strains, BALB/c and C57BL/6. Histology and hydroxyproline assays were performed to investigate liver morphology and fibrosis. Gene expression and signaling were analyzed by microarray, qPCR and Western blotting.ResultsExpression of HBV surface proteins in the liver of transgenic mice induced activation of protein kinase-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (eIF2α) phosphorylation. Phosphorylation of eIF2α resulted in activation of the ER stress markers glucose regulated protein (GRP) 78 and pro-apoptotic C/EBP homologous protein (CHOP) in transgenic mice on BALB/c genetic background leading to stronger liver injury and fibrosis in comparison with transgenic mice on C57BL/6 background. Hepatic stellate cells represented the main collagen-producing liver cells in HBV transgenic mice. The key regulators of hepatocyte proliferation, transcription factors c-Jun and STAT3 were activated in HBV transgenic mice. Tumour incidence in transgenic mice was strain- and sex-dependent.ConclusionsExtent of liver injury, fibrosis, and tumour development induced by hepatic HBV surface protein expression considerably depends on host genetic background.
Highlights
Chronic infection with hepatitis B virus (HBV) affects 350 to 400 million individuals worldwide and is the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide [1]
It is believed that these events originate from persistent immune pathogenesis [3], but observations in transgenic mouse models of HBV infection suggest that in absence of an adaptive immune responses cellular mechanisms induced by HBV proteins may lead to the development of these liver diseases [4,5]
The HBV surface (HBs) protein expression pattern in this mouse model mimics the situation in the liver of patients with enhanced intracellular expression and retention of Hepatitis B virus surface proteins, e. g. patients with Hepatitis B virus-related chronic liver disease treated by transplantation
Summary
Chronic infection with hepatitis B virus (HBV) affects 350 to 400 million individuals worldwide and is the leading cause of liver cirrhosis and hepatocellular carcinoma worldwide [1]. The HBV transgenic mice used in the current study contain a sub-genomic HBV DNA fragment (genotype D, subtype ayw) encoding the three co-carboxyterminal HBV surface (HBs) proteins under the control of the liver-specific murine albumin promoter [6]. These transgenic mice have been shown to develop chronic liver injury, regenerative hyperplasia, as well as adenomas and hepatocellular carcinomas (HCC) [7,8] the mechanisms of HBs proteins pathogenicity are poorly understood. We have investigated pathological cellular effects of HBV surface protein expression in the liver of transgenic mice with different genetic background
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